This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SPECIFIC AIMS: Phase I: 1. To define the maximum tolerated dose of R115777, OSI-774, or CCI-779 in combination with a fixed dose of BAY 43-9006, in patients with recurrent glioblastoma or gliosarcoma who are not taking enzyme-inducing antiepileptic drugs (EIAEDs). 2. To characterize the safety profile of the doublet combinations of R115777-BAY 43-9006, OSI-774-BAY 43-9006 and CCI-779-BAY 43-9006 in patients with recurrent glioblastoma or gliosarcoma. 3. To characterize the pharmacokinetics of these doublet combinations, evaluating single agent pharmacokinetics of each agent then the combination pharmacokinetics to determine drug-drug interactions. Phase II: 1. To determine the efficacy of each of the doublet combinations in patients with recurrent glioblastoma or gliosarcoma as measured by 6-month progression-free survival. 2. To determine the efficacy of each of the doublet combinations in patients with recurrent glioblastoma or gliosarcoma as measured by 12-month survival and objective tumor response. 3. To further characterize the safety profile of each of the doublet combinations. 4. To characterize the pharmacokinetics of each of the doublet combinations in a subset of the phase II patients to further define possible drug-drug interactions. 5. To perform exploratory correlative laboratory studies by examining tissue markers of signal transduction pathways by immunohistochemical analysis using tissue blocks obtained prior to initiation of protocol therapy, either from the time of diagnosis or subsequent tumor resection. 6. For the Molecular Targeted Combinations Correlative (MTC2) Study Initiative: To determine the relationship between tumor and blood biomarkers and clinical outcome of patients treated with the combination of targeted agents.